Autoradiographic analyses of agonist binding to muscarinic receptor subtypes.
Autoradiographic analyses of agonist binding to muscarinic receptor subtypes.
复制标题
与毒蕈碱受体亚型结合的激动剂的放射自显影分析。
DOI：
10.1016/0006-2952(89)90239-6
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发表时间：
1989
影响因子：
5.8
通讯作者：
Hoss,W
中科院分区：
文献类型：
--
作者：
MesserJr,WS;Ellerbrock,B;Price,M;Hoss,W
用定量放射自显影技术检测了四种M受体激动剂与大鼠脑区的结合。根据氧化曲莫林、槟榔碱、匹罗卡品和山茶酚在毒鼠碱第二信使系统中的不同效力和效果，选择了它们。总体而言，抑制[3 H]-L-苯甲酸奎宁酯([3 H]-L-QNB)与大鼠脑片结合的药效顺序为羟甲喋呤=槟榔碱；匹罗卡品=槟榔碱。对激动剂效力的区域性分析表明，所有激动剂对脑干和丘脑区域的选择性比对海马区和皮质区域的选择性更高。激动剂对脑室旁丘脑和上丘等区域的高选择性，也显示出对哌仑西平的低亲和力，这表明毒鼠碱激动剂与M2受体具有较高的亲和力。在4种受体激动剂中，匹罗卡品对M2受体的选择性最低，其在海马区和纹状体的IC50值(如CA3：40.6±9.4μM)仅比丘脑和脑干区(如：室旁丘脑：14.9±6.2μM)高3倍。氧化曲莫林对脑干和丘脑的选择性是脑干和丘脑的8倍，槟榔碱和山梨醇分别是脑干和丘脑受体的19倍和100倍。Scatchard分析显示，在单个脑区内，一些激动剂的结合谱不同，这表明即使在以M1或M2为主的受体区域内，也存在多个激动剂位置。例如，槟榔碱在大脑皮层外层、海马CA1层(主要是M1亚型)和脑室旁丘脑(主要是M2亚型)内显示弯曲的Scatchard曲线。激动剂识别单个区域内多个位置的能力可能反映了识别通过G蛋白耦合或解偶联到第二信使系统的受体的能力
The binding of four muscarinic receptor agonists to regions of rat brain was examined through quantitative autoradiographic techniques. Oxotremorine, arecoline, pilocarpine and bethanechol were chosen based on their different potencies and efficacies in muscarinic second messenger systems. Overall, the order of potency for inhibition of [3 H]-l-quinuclidinyl benzilate ([3 H]-l-QNB) binding to rat brain slices was oxotremorine> pilocarpine= arecoline> bethanecol. Regional assays of agonist potency indicated that all agonists were more selective for brainstem and thalamic regions than for hippocampal and cortical regions. The high selectivity of agonists for areas such as the paraventricular thalamus and the superior colliculus, which also display low affinity for pirenzepine, suggests that muscarinic agonists bind with higher affinity to M 2 receptors. Of the four agonists examined, pilocarpine displayed the lowest selectivity for M 2 receptors in that ic 50 values for pilocarpine were only 3-fold higher in the hippocampal and striatal regions (eg CA3: 40.6±9.4 μM) than in thalamic and brainstem regions (eg paraventricular thalamus: 14.9±6.2 μM). Oxotremorine was 8-fold more potent in the brainstem and thalamus, while arecoline and bethanechol were, respectively, 19-and 100-fold more selective for brainstem and thalamic receptors. Scatchard analyses revealed heterogeneous binding profiles for some agonists within single brain regions, suggesting that multiple agonist sites exist even within regions of predominately M 1 or M 2 receptors. For example, arecoline displayed curved Scatchard plots within the external layers of the cerebral cortex, layer CA1 of the hippocampus (predominantly M 1 subtype), and the paraventricular thalamus (predominantly M 2 subtype). The ability of agonists to recognize multiple sites within a single region may reflect the ability to recognize receptors coupled or uncoupled to second messenger systems through G-proteins